Noncarcinogenic chemotherapy with a combination of vincristine, methotrexate and 5-fluorouracil (VMF) in rats

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Abstract
The CMF regimen, which is clinically used in adjuvant therapy of breast cancer, is known to be carcinogenic in rats (Habs and Schmähl, 1981). To examine alternative regimens, a long‐term carcinogenicity study was performed, using the VMF regimen as follows: V (i.v.), M (i.p.) and F (p.o.) at 0.8, 20 and 300 mg/m2, respectively. These doses and a half‐dose regimen (0.5 VMF) were administered every 6 weeks to 80 rats (40 males, 40 females) in each of three groups. Group I served as an untreated control. Groups II, III and IV received 6 × VMF, 18 × 0.5 VMF and 18 × VMF, respectively. Unlike treatment with comparable doses of CMF, the present therapy did not result in an increased tumor rate or a change in tumor type over controls. The chemotherapeutic efficacy of VMF was compared with that of CMF by administering the following doses (mg/m2 i.p.) to groups of 20 rats bearing methylni‐trosourea‐induced primary mammary carcinomas: group I: C (420), 2: V (2.1), 3: M (35) and F (350), 4: C (210), M (21) and F (280), 5: V (1.05), M (21) and F (280), 6: as in 4 except that C was given 24 h prior to M and F, 7: as in 5 except that V was given 24 h prior to M and F, 8: ovariectomy on day 1, 9: control group. Animals bearing a tumor volume of ⩾ 0.8 cm3 were randomly allocated to the individual groups (day 1) and subsequently treated on days 1,8, 15 (V only) 22, and 29. After 5 weeks the following T/C values were recorded: group I: 12.6%, 2:80%, 3:49%, 4: 42.8%, 5: 67%, 6: 49.2%, 7: 26.5%, 8: 45.5%. These results indicate a possible superiority of VMF over CMF, since the former exhibits little or no carcinogenicity at comparable therapeutic activity.